Gazyvaro (obinutuzumab)

Gazyvaro (obinutuzumab)

Therapeutic indication

Adult patients with Chronic Lymphocytic Leukaemia (CLL)

Mechanism of action

Obinutuzumab is a recombinant monoclonal humanised and glycoengineered Type II anti‑CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B and mature B-lymphocytes, but not on haematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering of the Fc part of obinutuzumab results in higher affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells, macrophages and monocytes as compared to non-glycoengineered antibodies.

Therapeutic indication

Chronic lymphocytic leukaemia (CLL)

Gazyvaro in combination with chlorambucil for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy.

Follicular lymphoma (FL)

Gazyvaro in combination with chemotherapy, followed by Gazyvaro maintenance therapy in patients achieving a response, for the treatment of patients with previously untreated advanced FL.

Gazyvaro in combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Reimbursment modalities

Gazyvaro in CLL:

Gazyvaro in FL:


Administration and dosage

Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available.

 

Posology

Prophylaxis and premedication for tumour lysis syndrome (TLS)

Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12‑24 hours prior to start of Gazyvaro infusion as per standard practice. Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.

Prophylaxis and premedication for infusion related reactions (IRRs)

Premedication to reduce the risk of infusion related reactions is outlined in Table 1. Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle (see Table 1). Premedication for subsequent infusions and other premedication should be administered as described below.

Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration.

Dose

Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil)

For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2.

Duration of treatment

Six treatment cycles, each of 28 day duration.

Delayed or missed doses

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyvaro should be maintained between doses.

Follicular lymphoma  (FL, in combination with bendamustine) 

For patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen, the recommended dose of Gazyvaro in combination with bendamustine is shown in Table 3.

Duration of treatment

Induction treatment of approximately six months (six treatment cycles of Gazyvaro, each of 28 day duration when combined with bendamustine) followed by maintenance once every 2 months for 2 years or until disease progression (whichever occurs first).

 

Delayed or missed doses 

If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose.

If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1.

During maintenance, maintain the original dosing schedule for subsequent doses.

 

Dose modifications

In general, no dose reductions of Gazyvaro are recommended.

                Toxicity

No dose reductions of Gazyvaro due to toxicities are recommended.

                Hepatic impairment

The safety and efficacy of Gazyvaro in patients with impaired hepatic function has not been established. No specific dose recommendations can be made.

                Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance [CrCl] 30‑89 mL/min). The safety and efficacy of Gazyvaro has not been established in patients with severe renal impairment (CrCl < 30 mL/min).

                Drug-drug interactions

No dose reductions of Gazyvaro due to drug-drug interactions are recommended.

                Drug-food interactions

This information is not available.

 

Adverse events of special interest

Infusion related reactions 

Most frequently reported (≥ 5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported.

Chronic Lymphocytic Leukaemia 

The incidence of IRRs was higher in the Gazyvaro plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 65% with the infusion of the first 1,000 mg of Gazyvaro (20% of patients experiencing a Grade 3‑4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyvaro. The incidence of IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3‑5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.

In patients who received the recommended measures for prevention of IRRs, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented.

 

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

Grade 3-4 IRRs occurred in 12% of patients. In Cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyvaro plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyvaro plus chemotherapy, the incidence of IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyvaro alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the Gazyvaro and the relevant comparator arms. Overall, 3% of patients experienced an infusion related reaction leading to discontinuation of Gazyvaro.

 

Neutropenia and infections

 

Chronic Lymphocytic Leukaemia

The incidence of neutropenia was higher in the Gazyvaro plus chlorambucil arm (41%) compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte-colony stimulating factors. The incidence of infection was 38% in the Gazyvaro plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3‑5 events reported in 12% and 14%, respectively and fatal events reported in < 1% in both treatment arms). Cases of prolonged neutropenia (2% in the Gazyvaro plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyvaro plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the Gazyvaro plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 7%, respectively. The incidence of infection was 81% in the Gazyvaro plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections.

Thrombocytopenia and haemorrhagic events

 

Chronic Lymphocytic Leukaemia

The incidence of thrombocytopenia was higher in the Gazyvaro plus chlorambucil arm (15%) compared to the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated with Gazyvaro plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyvaro infusion). The overall incidence of haemorrhagic events was similar in the Gazyvaro treated arm and in the rituximab treated arm. The number of fatal haemorrhagic events was balanced between the treatment arms; however, all of the events in patients treated with Gazyvaro were reported in Cycle 1. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma 

The incidence of thrombocytopenia was 14%. Thrombocytopenia occurred more frequently in Cycle 1 in the Gazyvaro plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients in the Gazyvaro plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 5% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients; none of the fatal adverse events occurred in Cycle 1.

 

Progressive multifocal leukoencephalopathy 

PML has been reported in patients treated with Gazyvaro.

Hepatitis B reactivation 

Cases of hepatitis B reactivation have been reported in patients treated with Gazyvaro.

Gastro-Intestinal Perforation 

Cases of gastro-intestinal perforation have been reported in patients receiving Gazyvaro, mainly in iNHL. In the pivotal studies in iNHL up to 1% of patients experienced gastrointestinal perforation.

Worsening of pre-existing cardiac conditions

Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyvaro. These events may occur as part of an IRR and can be fatal.

Laboratory abnormalities

Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyvaro.

Management of adverse events

Management of IRRs may require temporary interruption, reduction in the rate of infusion, or treatment discontinuations of Gazyvaro as outlined below (see also section 4.4).

·           Grade 4 (life threatening): Infusion must be stopped and therapy must be permanently discontinued.

·           Grade 3 (severe): Infusion must be temporarily stopped and symptoms treated. Upon resolution of symptoms, the infusion can be restarted at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

The infusion must be stopped and therapy permanently discontinued if the patient experiences a second occurrence of a Grade 3 IRR.

·           Grade 1‑2 (mild to moderate): The infusion rate must be reduced and symptoms treated. Infusion can be continued upon resolution of symptoms and, if the patient does not experience any IRR symptoms, the infusion rate escalation can resume at the increments and intervals as appropriate for the treatment dose (see Tables 4 and 5). For CLL patients receiving the Day 1 (Cycle 1) dose split over the two days, the Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

 

Initial work-up before start of treatment

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Concomitant Treatment 

No formal drug-drug interaction studies have been performed, although limited drug-drug interaction sub-studies have been undertaken for Gazyvaro with bendamustine and chlorambucil.

A risk for interactions with other concomitantly used medicinal products cannot be excluded.

 

Pharmacokinetic interactions

Obinutuzumab is not a substrate, inhibitor, or inducer of cytochrome P450 (CYP450), uridine diphosphate glucuronyltransferase (UGT) enzymes and transporters such as P-glycoprotein. Therefore, no pharmacokinetic interaction is expected with drugs known to be metabolised by these enzyme systems.

Co-administration with Gazyvaro had no effect on the pharmacokinetics of bendamustine or chlorambucil. In addition, there were no apparent effects of bendamustine or chlorambucil on the pharmacokinetics of Gazyvaro.

Pharmacodynamic interactions

 

Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery because of the immunosuppressive effect of obinutuzumab.

The combination of obinutuzumab with chlorambucil or bendamustine may increase the risk of neutropenia.

Response evaluation

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References


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